Project Summary/Abstract More than half of all cancer patients receive definitive radiotherapy (RT), usually with x-rays. Particle beam radiation therapy (PBRT) with low linear energy transfer (LET) protons is increasingly being used based on the assumption they can reduce complications and improve local control. High-LET PBRT, e.g., with carbon ions, may provide additional physical dose distribution advantages over low-LET RT. In addition, carbon and neon may yield an increased level of effectiveness against radioresistant and hypoxic (poorly oxygenated) tumor cells, which represent the most RT- and chemotherapy-resistant aggressive tumor cells. Adult patients with advanced tumors of the lung, head and neck, brain, esophagus, and pancreas may especially benefit from the advantages of high-LET ions, but the studies conducted to date have not been definitive. To justify the development of an expensive PBRT facility with high-LET ions, definitive studies (i.e., randomized trials) are needed to prove that high-LET ion beam RT results in improved outcomes compared to treatment with low- LET protons or advanced x-ray based therapy such as intensity modulated radiation (IMRT) or stereotactic body radiotherapy (SBRT). The North American Particle Therapy Alliance (NAPTA) brings together experts in radiation oncology, medical and accelerator physics, magnet design, and radiobiology with international consultants from the existing ion beam facilities in Germany, Italy, and Japan. The main objective of NAPTA is to build a future for ion therapy in the U.S. by integrating and developing the required clinical, biological and technical expertise. In this initial two-year funding period, we will: 1) form a network of teams with a common vision for R&D and clinical studies involving PBRT; 2) enhance clinical PBRT research by developing the infrastructure for treating all patients within common protocols shared by all partner institutions; 3) facilitate the development of new, low-cost, compact/efficient designs for ion accelerators, ion gantries, treatment planning systems, and imaging technology; and 4) facilitate the development of new knowledge in radiobiology related to PBRT, by integration of currently ongoing projects and startup of collaborations with access to existing facilities with protons and ions.